Aza-amino acid derivatives (factor Xa inhibitors 15)

ABSTRACT

The invention relates to semicarbazides of the general formula I  
                 
 
     where R 1 , R 2 , R 3 , R 4  and I have the meaning indicated in claim 1.  
     The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, mycocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

[0001] The invention relates to semicarbazides of the general formula I,

[0002] where:

[0003] R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or —C(═NH)—NH₂,which can also be monosubstituted by —OH, —OCOOA, —OCOO(CH₂)_(n)N(A)₂,—OCOO(CH₂)_(m)-Het, —CO—C(A)₂—R⁵, —COOA, —COSA, —COOAr, —COOAr′ or by

[0004] R² is H, COOA,

[0005] R³ is unbranched, branched or cyclic alkyl having 1-20 C atoms,in which one or two CH₂ groups can be replaced by O or S atoms, or isAr, Ar′, X or Hal,

[0006] R⁴ is phenyl monosubstituted by S(O)_(k)A, S(O)_(k)NHA, CF₃,COOA, CH₂NHA, CN or OA,

[0007] R⁵ is —CHal₃, —O(C═O)A or

[0008] Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA,S(O)_(n)NA₂,

[0009] Ar′ is —(CH₂)_(n)—Ar,

[0010] Het is a mono- or binuclear, saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, whichcan be unsubstituted or substituted by A,

[0011] A is H, unbranched, branched or cyclic alkyl having 1-20 C atoms,

[0012] X is —(CH₂)_(n)—Y,

[0013] Y is COOA,

[0014] Hal is F, Cl, Br or I,

[0015] n is 1, 2, 3, 4, 5 or 6,

[0016] m is 0 or 1,

[0017] k is 0, 1 or 2,

[0018] l is 0, 1, 2, 3 or 4,

[0019] and their pharmaceutically tolerable salts and solvates.

[0020] The invention also relates to the optically active forms, theracemates, the diastereomers and also the hydrates and solvates, e.g.alcoholates, of these compounds.

[0021] For the control of hemorrhages caused by injuries, the human bodyhas a mechanism by means of which, with the aid of blood clots, a rapidwound closure is achieved. Blood clots are formed by a series of zymogenactivations. In the course of this enzymatic cascade, the activated formof a factor in each case catalyzes the activation of the next. Sincethis process is of catalytic nature, very small amounts of thetriggering factor suffice to set the cascade in motion. As a result ofthe large number of steps, a large amplification is achieved, whichguarantees a rapid response to the injury. The plasmatic clotting aftera tissue lesion can take place exogenously due to the release of tissuethrombokinase. The corresponding reaction sequence is designated as anextravascular system (extrinsic system) and proceeds within seconds. Theclotting can also be triggered endogenously by thrombocytolysis. Thisreaction sequence, which is designated as an intravascular system,proceeds within minutes. Both systems result in a final common sequenceof steps which lead to the formation of a blood clot. The intravascularand the extravascular system have a mutual influence in vivo. Both arenecessary for the complete course of blood clotting.

[0022] Rapid blood clotting is so important for the closure of injuries,in certain disorders it is actually necessary to inhibit blood clottingin order, for example, to avoid the formation of thrombi in vessels. Inthis case, an intervention should be made as specifically andselectively as possible into the blood clotting cascade in order to beable to control the inhibition as precisely as possible and to be ableto avoid undesired side effects.

[0023] Factor X_(a) is a serine protease of the blood clotting cascade,which is formed by activation of factor X. In the intravascular pathway,this activation is carried out by factor IX_(a), this reaction beingstimulated by the antihemophilic factor (VIII_(a)). By means of factorX_(a), prothrombin is then converted into thrombin. The proteolyticenzyme thrombin cleaves fibrinogen into fibrin monomers, which arrangespontaneously to give ordered fibrous structures, which are designatedas fibrin. The clot that results due to the spontaneous aggregation offibrin monomers is stabilized by covalent crosslinkages between the sidechains of various molecules in the fibrin fibers. To this end, peptidebonds are formed between specific glutamine and lysine side chains in atransamidation reaction. This crosslinkage is catalyzed by an enzymewhich is designated as factor XIII_(a).

[0024] In the extravascular system, the activation of factor X iscarried out by the tissue factor and factor VII.

[0025] Inhibition of factor X_(a) allows specific intervention intoblood clotting, since no other processes are influenced here. It is moreadvantageous than, for example, inhibition of thrombin, since thrombinon the one hand catalyzes the conversion of fibrinogen to fibrin, andalso the conversions of factor VIII into factor VIII_(a), factor V intoV_(a) and factor XI into XI_(a), and on the other hand, for example,also activates platelets. A variety of research activities havetherefore been undertaken to develop inhibitors of factor X_(a), whichhave led to the development of various classes of substance.

[0026] WO 99/11657 describes 1-amino-7-isoquinoline derivatives whichact as inhibitors of serine proteases. WO 99/11658 describem-benzamidine derivatives which act as serine protease inhibitors.Furthermore, WO 99/10316 describes 3-amidinoaniline derivatives whichact as inhibitors of activated blood clotting factor X_(a).

[0027] It is an object of the invention to discover novel compoundshaving valuable properties, in particular those which can be used forthe production of medicaments.

[0028] It has been found that the compounds of the formula I and theirsalts have very valuable pharmacological properties, together with goodtolerability. In particular, they exhibit factor X_(a)-inhibitingproperties and can therefore be employed for the control and preventionof thromboembolic disorders, such as thrombosis, myocardial infarct,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and intermittent claudication.

[0029] The compounds of the formula I according to the invention canfurthermore be inhibitors of the blood clotting factors VII_(a), IX_(a)and thrombin of the blood clotting cascade.

[0030] The inhibition of thrombin can be measured, for example, by themethod of G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

[0031] The inhibition of factor X_(a) by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A suitable procedure is described, for example, by J. Hauptmannet al. in Thrombosis and Haemostasis, 1990, 63, 220-223.

[0032] The measurement of the inhibition of factor X_(a) can be carriedout, for example, according to the method of T. Hara et al. in Thromb.Haemostas., 1994, 71, 314-319.

[0033] The inhibition of factor VII_(a) by the compounds according tothe invention and the measurement of the anticoagulant andantithrombotic activity can be determined according to customary invitro or in vivo methods. A customary procedure for the measurement ofthe inhibition of factor VII_(a) is described, for example, by H. F.Ronning et al. in Thrombosis Research 1996, 84, 73-81.

[0034] The inhibition of factor IX_(a) by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined according to customary in vitro or in vivomethods. A suitable procedure is described, for example, by J. Chang etal. in Journal of Biological Chemistry 1998, 273, 12089-12094.

[0035] The compounds of the formula I can be employed as pharmaceuticalactive compounds in human and veterinary medicine, in particular for thecontrol and prevention of thromboembolic disorders such as thrombosis,myocardial infarct, arteriosclerosis, inflammation, apoplexy, anginapectoris, restenosis after angioplasty and/or intermittent claudication.Furthermore, they are applicable for the treatment of tumors, tumordiseases and/or tumor metastases. A relation between the tissue factorTK/factor VIIa and the development of various types of cancer has beenshown by T. Taniguchi et al. in Biomed. Health Res. (2000), 41(“Molecular Pathogenesis of Pancreatic Cancer”), 57-59.

[0036] The semicarbazides according to the invention particularlypreferably have a structure of the formula II

[0037] where R¹, R³, A and k have the meaning indicated in claim 1 and Wis S(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CN or OA.

[0038] Compounds which are particularly to be emphasized are mentionedbelow:

[0039]4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1),

[0040]4′-[3-(3-(N²-hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2),

[0041]4′-[3-(3-amidinophenyl)-2-methylcarbazoylamino]biphenyl-2-sulfonamide(3),

[0042]1-(3-amidinophenyl)-2-methyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(4),

[0043]4′-[3-(3-amidinophenyl)-2-ethylcarbazoylamino]biphenyl-2-sulfonamide(5),

[0044]1-(3-amidinophenyl)-2-ethyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(6),

[0045]4′-[3-(3-amidinophenyl)-2-isopropylcarbazoylamino]biphenyl-2-sulfonamide(7),

[0046]1-(3-amidinophenyl)-2-isopropyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(8),

[0047]4′-[3-(3-amidinophenyl)-2-butylcarbazoylamino]biphenyl-2-sulfonamide(9),

[0048]1-(3-amidinophenyl)-2-butyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(10),

[0049]4′-[3-(3-amidinophenyl)-2-isobutylcarbazoylamino]biphenyl-2-sulfonamide(11),

[0050]1-(3-amidinophenyl)-2-isobutyl4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(12),

[0051]4′-[3-(3-amidinophenyl)-2-pentylcarbazoylamino]biphenyl-2-sulfonamide(13),

[0052]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-pentylsemicarbazide(14),

[0053]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide(15),

[0054]4′-[3-(3-amidinophenyl)-2-(2-butyl)carbazoylamino]biphenyl-2-sulfonamide(16),

[0055]1-3-amidinophenyl)-2-(2-butyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(17),

[0056]4′-[3-(3-amidinophenyl)-2-(cyclohexylmethyl)carbazoylamino]biphenyl-2-sulfonamide(18),

[0057]1-(3-amidinophenyl)-2-(cyclohexylmethyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(19),

[0058]4′-[3-(3-amidinophenyl)-2-benzylcarbazoylamino]biphenyl-2-sulfonamide(20),

[0059]1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(21),

[0060]1-(3-N-2-hydroxyamidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(22),

[0061]4′-[3-(3-amidinophenyl)-2-phenylcarbazoylamino]biphenyl-2-sulfonamide(23),

[0062]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylsemicarbazide(24),

[0063] methylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(25),

[0064] 2,2,2-trichloroethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(26),

[0065] S-ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]thiocarbamate(27),

[0066] 4-methoxybenzylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(28),

[0067] ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(29),

[0068] propylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(30),

[0069] butylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(31),

[0070] isopropylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(32),

[0071] isobutylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(33),

[0072] allylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(34),

[0073] phenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(35),

[0074] 2-fluorophenylN-[3-[2-benzyl4-(2′-methylsulfonylbiphenyl4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(36),

[0075]2-benzyl-1-[3-(N′-(methylcarboxy)amidino)phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(37),

[0076]2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-1-[3-(N′-(phenylcarboxy)amidino)phenyl]semicarbazide(38),

[0077]2-benzyl-1-[3-(N′-(isobutylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(39),

[0078]2-benzyl-1-[3-[N′-(2-methylcarboxy-2-propoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(40),

[0079]2-benzyl-1-[3-[N′-(1-(methylcarboxy)ethoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(41),

[0080] 1-methyl-4-piperidinylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(42),

[0081] 2-(4-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(43),

[0082] 5-methyl-2-oxo-1,3-dioxol-4-ylmethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(44),

[0083] 2-(3-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(45),

[0084] 2-(N,N-diethylamino)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(46),

[0085] 2-(N-morpholinyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(47),

[0086]1-(3-amidinophenyl)-2-(2-fluorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(48),

[0087]1-(3-amidinophenyl)-2-(2-methylbenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(49),

[0088]1-(3-amidinophenyl)-2-(2-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)semicarbazide(50),

[0089]1-(3-amidinophenyl)-2-(3-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(51),

[0090]4-[1-(3-amidinophenylamino)-3-(2′-methylsulfonylbiphenyl-4-yl)ureidomethyl]-benzoicacid (52),

[0091]1-(3-amidinophenyl)-2-(3-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(53),

[0092]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(54),

[0093]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide (55),

[0094]1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethoxybenzyl)semicarbazide(56),

[0095]1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)semicarbazide(57),

[0096]1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(58),

[0097]1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(59),

[0098]1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(60),

[0099]1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(61),

[0100]1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)semicarbazide(62),

[0101]1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(63),

[0102]1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(64),

[0103]1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(65),

[0104] ethyl2-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl4-yl)ureido]-acetate(66),

[0105] ethyl3-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl4-yl)ureido]-propionate(67),

[0106]4′-[3-(3-amidinophenyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]carbazoylamino]-biphenyl-2-sulfonamide(68),

[0107]4′-[3-(3-amidinophenyl)-2-(2-methoxyethyl)carbazoylamino]biphenyl-2-sulfonamide(69),

[0108]4′-[3-(3-amidinophenyl)-2-(methoxymethyl)carbazoylamino]biphenyl-2-sulfonamide(70),

[0109]4′-[3-(3-amidinophenyl)-2-(4-methoxybutyl)carbazoylamino]biphenyl-2-sulfonamide(71),

[0110]1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(72),

[0111]1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(73),

[0112]1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(74),

[0113]1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(75),

[0114]1-(3-aminomethylphenyl)-2-benzyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)semicarbazide(76),

[0115]1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(77),

[0116]1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(78),

[0117]1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(79).

[0118]1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(80),

[0119]1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(81),

[0120]1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)semicarbazide(82),

[0121]1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(83),

[0122]1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(84),

[0123]1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(85),

[0124]1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(86),

[0125]1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(87),

[0126]1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(88),

[0127]2-Benzyl-1-[3-(N¹-methoxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(89),

[0128]2-Benzyl-1-[3-(N¹-ethoxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(90),

[0129]2-Benzyl-1-[3-(N¹-vinyloxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(91),

[0130]2-Benzyl-1-[3-(N¹-benzyloxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(92),

[0131]2-Benzyl-1-[3-(N¹-isopropoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(93),

[0132]1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(94),

[0133]1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(95),

[0134]1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(96),

[0135]1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(97),

[0136]1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(98),

[0137]1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(99),

[0138]1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(100),

[0139]1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3,5-difluorobiphenyl-4-yl)-semicarbazide(101),

[0140]1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl4-yl)-semicarbazide(102),

[0141]1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl4-yl)-semicarbazide(103),

[0142]1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(104).

[0143] Particular embodiments of the compounds of the formula I arementioned below, a generalized form of the group of compounds beingindicated in the tables.

[0144] The coefficients indicated in the formulae correspond to themeanings indicated above. In the case of the examples synthesized forthe individual groups of compounds, the FAB values measured areindicated in each case if available.

[0145] In table 1, examples are mentioned for compounds in which thevarious alkyl radicals R³ are introduced into the molecular structure.In the diphenyl moiety, the sulfonamide derivatives and themethylsulfonyl derivatives were prepared by variation of the group Y,which is an amino or a methyl group. TABLE 1

Number R¹ R³ Z FAB 1

—NH₂ 467 2

—NH₂ 483 3

—NH₂ 4

—CH₃ 5

—NH₂ 6

—CH₃ 7

—NH₂ 8

—CH₃ 9

—NH₂ 10

—CH₃ 11

—NH₂ 12

—CH₃ 13

—NH₂ 14

—CH₃ 15

—CH₃ 446

[0146] Examples in which the radical R³ is constructed as a cycloalkylradical or as an aromatic radical are shown in table 2. Here too,sulfonamide derivatives and methylsulfonyl derivatives were prepared byvariation of the group Z. TABLE 2

Number R¹ R³ Z FAB 16

—NH₂ 17

—NH₂ 18

—NH₂ 19

—CH₃ 20

—NH₂ 515 21

—CH₃ 514 22

—CH₃ 530 23

—NH₂ 24

—CH₃

[0147] The compounds of the formula I can also be constructed asprodrugs. After absorption into the blood circulation, the compounds arecleaved enzymatically and the active compound is released. In table 3,various possibilities for prodrugs are presented with the aid of anactive compound.

[0148] The absorption rate and the rate of release of the activecompound, for example, can be influenced by the variation of the radicalR¹. The examples of the group R¹ indicated in table 3 can be transferredwithout problems to other active compounds of the formula 1, such as,for example, are shown in tables 1 and 2. TABLE 3

Number R¹ FAB 25

572 26

690 27

28

678 29

586 30

31

614 32

600 33

614 34

598 35

634 36

652

[0149] Further examples of variation of the radical R¹ for preparationof prodrugs are indicated in table 4. The preparation of the prodrugsshown in tables 3 and 4 is carried out analogously to the procedureswhich are described in S. N. Rahamthullah et al J. Med. Chem. 1999, 42,3994-4000. TABLE 4 Number R¹ FAB 37

572 38

634 39

614 40

672 41

42

692 43

44

45

46

47

89

90

91

92

99

[0150] By substitution of the alkyl or aryl groups introduced as theradical R³ by, for example, halogen atoms, alkyl groups or carboxylgroups, the polarity of the molecule can be influenced. The compoundbecomes more lipophilic as a result of the introduction of fluorineatoms and is therefore more easily absorbed. Examples of compounds ofthis type are shown in table 5. In this case, the group R³ was variedfor a specific active compound. A variation of this type can also becarried out without problems for other radicals R¹ and R⁴. TABLE 5

Number R³ B C FAB 48

H H 49

H H 50

H H 51

H H 52

H H 53

H H 54

H H 582 55

H H 582 56

H H 57

H F 532 58

H F 600 59

H F 600 60

H H 582 61

H F 600 62

F F 550 63

F F 618 64

F F 618 65

F F 618

[0151] Further examples of the radicals R³ which contain heteroatoms areshown in table 6. The variation of the radical R³ was in this caseperformed by way of example on a sulfonamide derivative. TABLE 6

Number R³ FAB 66

67

68

69

70

71

[0152] Examples in which the lipophilicity of a part of the compoundswas varied are shown in table 7. Here, in a part of the compounds, theradical R³ includes a trifluoromethyl group. Furthermore, in some of thecompounds, one or two fluorine atoms were introduced into the biphenylmoiety of the molecule. The variation can be transferred to the othercompounds of the formula I without problems. TABLE 7

Number R³ B C RAB 72

H H 73

H H 74

H H 75

H H 76

F H 77

F H 78

F H 79

F H 587 80

H H 569 81

H H 569 82

F H 519 83

F H 587 84

H H 501 85

H F 587 86

F F 537 87

F F 605 88

F F 605

[0153] Further compounds are shown in table 8. TABLE 8

Number R³ B C FAB 94

H H 598 95

H H 598 96

F H 548 97

F H 616 98

F H 616 99

H H 598 100

F H 616 101

F F 566 102

F F 634 103

F F 634 104

F F 634

[0154] The structural elements of the compounds according to theinvention shown above with the aid of selected compounds can be combinedarbitrarily. The compounds can thereby be tailored to the intendedtherapeutic use.

[0155] The compounds of the formula I can be prepared by processes knownper se. Some exemplary synthesis routes are presented below.

[0156] The synthesis of the molecular structure is explained with theaid of scheme 1.

[0157] The synthesis starts from the bromobenzene derivative 501. Theradical R¹ is preferably a group which can be converted into an amidinogroup at a later point in time in the synthesis. Appropriate structuralelements are presented further below. The bromine forms the leavinggroup for the reaction with the protected hydrazine derivative 502 (WangZ. et al. Tetrahedron Lett. 1999, 40, 3543-3546). The bromine atom cantherefore also be replaced by other suitable leaving groups, for exampleother halides or sulfonates. The hydrazine derivative 502 has aprotective group P. The protective groups used can be customaryprotective groups for amino groups. A particularly suitable protectivegroup is the BOC protective group. The protected phenylhydrazinederivative 503 is obtained by reaction of the compounds 501 and 502. Thefree NH₂ group is protected in the next reaction step by the protectivegroup P′. The intermediate III is obtained. If possible, the protectivegroups P and P′ are chosen differently in order to make possibleselective deprotection of the two nitrogen atoms. The protective groupP′ used can, as explained above, be the protective groups for aminogroups known to the person skilled in the art. Next, the introduction ofthe radical R³ is carried out, in which, for example, the compound IIIis reacted with an alkyl halide to give the compound IV. Compound IV isthen selectively deprotected on the terminal nitrogen with obtainment ofthe compound V. By reaction with optionally F substituted iodophenylisocyanate, the compound VI is obtained. The iodine atom in compound VIcan be substituted, whereby the radical R⁴ can be introduced into themolecule. Compound VII is obtained. The radical R⁴ is present here insuitably protected form. Examples are illustrated further below.Together with the radicals R¹, P and R⁴, the compound VII in generaladditionally contains protected structural elements. The removal of theprotective group P is carried out according to customary processes, forexample using acid.

[0158] Scheme 2 shows suitable radicals R¹, which remain unchanged inthe reaction steps presented above and can then be released startingfrom compound VII. For reasons of clarity, only the phenyl group havingthe radical R¹ is shown in scheme 2.

[0159] The first possibility consists in the introduction of a nitrilegroup. This can be converted into the hydroxyamidino group (505) usinghydroxylammonium chloride and triethylamine. These compounds can alreadybe used as prodrugs. The amidino group (506) is released by reductionwith Raney nickel under a hydrogen atmosphere. The aminomethylderivative (512) is likewise formed from the nitrile (504) by reduction.

[0160] A further possibility is shown under b). This group (507) canlikewise be converted into the amidino group (506) using Raney nickeland hydrogen.

[0161] In scheme 3, possibilities are presented which allow theintroduction of a sulfonamide group (a) and of a methylsulfonyl group(b). Here too, for reasons of clarity only the essential molecularentity (R³) is shown.

[0162] For the protection of sulfonamides, the amino group is suitablyprotected. Under (a), the nitrogen, for example, is protected with atert-butyl group. The removal of the group is carried out using acid,e.g. trifluoroacetic acid.

[0163] To introduce the methylsulfonyl group, the correspondingmethylthio compound (510) is used as a starting compound. Starting fromthe corresponding compound VII, the methylthio group is oxidized to themethylsulfonyl compound 511, for example, using sodium perboratetrihydrate in acetic acid.

[0164] The reaction schemes indicated above can be varied by the personskilled in the art without problems. For example, other leaving orprotective groups can be employed. If racemic mixtures are obtained inthe reactions, diastereomers can be formed from these in the customarymanner by reaction with an optically active resolving agent, and arethen separated according to customary processes. A chromatographicresolution of enantiomers with the aid of an optically active resolvingagent (e.g. dinitrobenzylphenylglycine, cellulose triacetate or otherderivatives of carbohydrates or chirally derivatized methacrylatepolymers attached to kieselguhr) is also advantageous.

[0165] The invention further relates to the use of the compounds of theformula I and/or their physiologically acceptable salts for theproduction of pharmaceutical preparations, in particular by a nonchemical route. In this connection, they can be brought into a suitabledose form, together with at least one solid, liquid and/or semiliquidvehicle or excipient and if appropriate in combination with one or morefurther active compounds.

[0166] The invention further relates to pharmaceutical preparationscomprising at least one compound of the formula I and/or one of itsphysiologically acceptable salts.

[0167] These preparations can be used as medicaments in human orveterinary medicine. Possible vehicles are organic or inorganicsubstances which are suitable for enteral (e.g. oral) or parenteraladministration or topical application and do not react with the novelcompounds, for example water, vegetable oils, benzyl alcohols, alkyleneglycols, polyethylene glycols, glyceryl triacetate, gelatin,carbohydrates such as lactose or starch, magnesium stearate, talc andpetroleum jelly. In particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops are suitable fororal administration, suppositories are suitable for rectaladministration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are suitable forparenteral administration, and ointments, creams or powders are suitablefor topical application. The novel compounds can also be lyophilized andthe lyophilizates obtained used, for example, for the production ofinjection preparations. The preparations indicated can be sterilizedand/or can contain excipients, such as lubricants, preservatives,stabiizers and/or wetting agents, emulsifiers, salts for influencing theosmotic pressure, buffer substances, colorants, flavorings and/or one ormore further active compounds, e.g. one or more vitamins.

[0168] The compounds of the formula I and their physiologicallyacceptable salts can be used in the control and prevention ofthromboembolic disorders such as thrombosis, myocardial infarct,arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosisafter angioplasty and intermittent claudication.

[0169] As a rule, the substances according to the invention arepreferably administered here in doses of between 1 and 500 mg, inparticular between 5 and 100 mg, per dose unit. The daily dose ispreferably between approximately 0.02 and 10 mg/kg of body weight. Thespecific dose for each patient depends, however, on various factors, forexample on the efficacy of the specific compound employed, on the age,body weight, general state of health, sex, on the diet, on the time androute of administration, and on the excretion rate, pharmaceuticalcombination and severity of the particular disorder to which the therapyrelates. Oral administration is preferred.

[0170] The invention is illustrated in greater detail with the aid ofexamples.

EXAMPLE A: SYNTHESIS OF4′-[3-(3-AMIDINOPHENYL)-2-PROPYLCARBAZOYLAMINO]BIPHENYL-2-SULFONAMIDE 1

[0171] The synthesis is shown in scheme 4.

[0172] tert-Butyl 2-(3-cyanophenyl)carbazate 401

[0173] 50.0 g (0.275 mol) of 3-bromobenzonitrile in 400 ml of THF aretreated under a nitrogen atmosphere with 36.345 g (0.275 mol) oftert-butyl carbazate, 89.6 g (0.275 mol) of cesium carbonate, 1.581 g(0.003 mol) of bis(dibenzylideneacetone)palladium and 4.602 g (0.008mol) of 1,1′-bis(diphenylphosphino)ferrocene and the mixture is thenstirred at 110° C. for 18 h. After cooling and customary work-up, 15.8 g(24.7%) of 401 are obtained as an oil; MS(FAB)=234. [The reaction iscarried out analogously to a procedure of Wang et al. Tetrahedron Lett.1999, 40, 3543].

[0174] tert-Butyl 2-(3-cyanophenyl)-3-(2,2,2-trifluoroacetyl)carbazate402

[0175] 10.7 g (46 mmol) of 401 are treated with 9.54 ml (68.8 mmol) oftriethylamine in 200 ml of THF. 7.02 ml (50.46 mmol) of trifluoroaceticanhydride are slowly added dropwise with cooling to 5° C. After stirringfor 6 h, the mixture is worked up in the customary manner and 14.3 g(94.7%) of 402 are thus obtained as an oil, which is employed directlyin stage 3.

[0176] tert-Butyl2-(3-cyanophenyl)-3-propyl-3-(2,2,2-trifluoracetyl)carbazate 403

[0177] 5.0 g (15.19 mmol) of the crude product 402 are treated with 7.42g (22.77 mmol) of cesium carbonate in 100 ml of DMF under a nitrogenatmosphere. After 30 min, 3.87 ml (22.77 mmol) of 1-iodopropane areslowly added dropwise and the mixture is then stirred at RT for 18 h.After customary work-up, 5.64 g (100%) of 403 are thus obtained as anoil, which is employed directly in stage 4.

[0178] tert-Butyl 2-(3-cyanophenyl)-3-propylcarbazate 404

[0179] 5.64 g (15.187 mmol) of crude product 403 are dissolved in 100 mlof methanol and treated at RT with 10 ml of completely deionized waterand 1.08 g (45.24 mmol) of lithium hydroxide. The reaction mixture isthen stirred for 5 h. After customary work-up, 2.67 g (63.8%) of 404 arethus obtained as an oil; MS(FAB)=276.

[0180] tert-Butyl2-(3-cyanophenyl)-3-(4-iodophenylaminocarbonyl)-3-propylcarbazate 405

[0181] 2.0 g (7.273 mmol) of 404 are stirred at RT for 1.5 h in 5.0 mlof pyridine with 1.78 g (7.265 mmol) of 4-iodophenyl isocyanate. Aftercustomary work-up, 3.2 g (84.7%) of 405 are thus obtained as crystalshaving a melting point of 184-185° C.; MS(FAB)=521.

[0182]4′-[3-tert-Butoxycarbonyl-3-(3-cyanophenyl)-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide406

[0183] 1.5 g (2.883 mmol) of 405 and 1.112 g (4.324 mmol) of2-(t-butylamino-sulfonyl)phenylboronic acid are dissolved in 100 ml ofethylene glycol dimethyl ether, treated with 63 mg (0.086 mmol) ofPdCl₂(dppf) and 20.0 ml of 2N sodium carbonate solution and then stirredat 110° C. under a nitrogen atomsphere for 3 h. After customary work-up,1.32 g (75.6%) of 406 are thus obtained as crystals having a meltingpoint of 173-174° C.; MS(FAB)=606.

[0184]4′-[3-tert-Butoxycarbonyl-3-[3-(N¹-hydroxyamidino)phenyl]-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide407

[0185] A suspension of 1.0 g (1.651 mmol) of 406 in 25.0 ml of ethanolare treated with 0.459 g (6.604 mmol) of hydroxylammonium chloride and0.916 ml (6.604 mmol) of triethylamine and the mixture is stirred underreflux for 5 h. After customary work-up, 1.05 g (99.6%) of 407 are thusobtained as crystals having a melting point of 218-219° C.; MS(FAB)=639.

[0186]4′-[3-(3-Amidinophenyl)-3-tert-butoxycarbonyl-2-propylcarbazoylamino]-N-tert-butylbiphenyl-2-sulfonamide408

[0187] 0.7 g (1.096 mmol) of 407 is dissolved in 10.0 ml of methanol,treated with 0.25 ml of acetic acid and 0.3 g of water-moist Raneynickel and the mixture is stirred under an H₂ atmosphere for 18 h. Aftercustomary work-up, 0.62 g (90.8%) of 408 is thus obtained as crystalshaving a melting point of >300° C.; MS(FAB)=623.

[0188]4′-[3-(3-(N-2-HYdroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2)

[0189] 0.2 g (0.313 mmol) of 407 is dissolved in 5.0 ml oftrifluoroacetic acid and the solution is stirred at 5° C. for 18 h.After customary work-up, 0.15 g (99.3%) of 2 is thus obtained ascrystals having a melting point of 163-164° C.; MS(FAB)=483.

[0190]4′-[3-(3-Amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1)

[0191] 0.5 g (0.803 mmol) of 408 is dissolved in 5.0 ml oftrifluoroacetic acid and stirred at 5C for 18 h. After customarywork-up, 0.15 g (99.3%) of 1 is thus obtained as crystals having amelting point of 215-216° C.; MS(FAB)=467.

EXAMPLE B: SYNTHESIS OF1-(3-AMIDINOPHENYL)-4-(2′-METHYLSULFONYLBIPHENYL-4-YLAMINO)-2-PROPYLSEMICARBAZIDE15

[0192] The synthesis is shown in scheme 5:

[0193] tert-Butyl2-(3-cyanophenyl)-3-(2′-methylthiobiphenyl-4-ylaminocarbonyl)-3-propylcarbazate409

[0194] 1.5 g (2.883 mmol) of 405 and 0.968 g (5.766 mmol) of2-(methylthio)-phenylboronic acid are dissolved in 100 ml of ethyleneglycol dimethyl ether, treated with 63 mg (0.086 mmol) of PdCl₂(dppf)and 20.0 ml of 2N sodium carbonate solution and then stirred at 110° C.under a nitrogen atmosphere for 3 h. After customary work-up, 1.28 g(75.9%) of 409 are thus obtained as crystals having a melting point of184-185° C.; MS(FAB)=517.

[0195] tert-Butyl2-(3-cyanophenyl)-3-(2′-methylsulfonylbiphenyl-4-ylaminocarbonyl)-3-propylcarbazate410

[0196] 0.8 g (1.548 mmol) of 409 is suspended in 15 ml of acetic acidwith 1.433 g (9.312 mmol) of sodium perborate trihydrate and the mixtureis stirred at 60° C. for 18 h. After customary work-up, 0.65 g (76.5%)of 410 is thus obtained as crystals having a melting point of 194-195°C.; MS(FAB)=549.

[0197] tert-Butyl 2-[3-(N¹-hydroxyamidino)phenyl]-3-(2′-methylsulfonylbiphenyl-4-ylaminocarbonyl)-3-propylcarbazate411

[0198] A solution of 0.6 g (1.094 mmol) of 410 is dissolved in 25 ml ofethanol, treated with 0.304 g (4.376 mmol) of hydroxylammonium chlorideand 0.608 ml of (4.376 mmol) of triethylamine and then stirred underreflux for 18 h. After customary work-up, 0.11 g (17.3%) of 411 is thusobtained as crystals having a melting point of 187-188° C.; MS(FAB)=582.

[0199]1-(3-N²-Hydroxyamidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide413

[0200] 50.0 mg (0.086 mmol) of 411 are dissolved in 1.0 ml of 4N HCl indioxane. and the solution is stirred at RT for 18 h. After customarywork-up, 0.11 g (17.3%) of 413 is thus obtained as crystals having amelting point of 195-196° C.; MS(FAB)=482.

[0201] tert-Butyl2-(3-amidinophenyl)-3-(2′-methylsulfonylbiphenyl4-ylaminocarbonyl)-3-propylcarbazate412

[0202] 0.2 g (0.344 mmol) of 411 is dissolved in 5.0 ml of methanol,treated with 0.1 ml of acetic acid and 0.1 g of water-moist Raney nickeland the mixture is stirred under an H₂ atmosphere for 18 h. Aftercustomary work-up, 0.19 g (100%) of 412 is thus obtained as crystalshaving a melting point of >300° C.; MS(FAB)=566.

[0203]1-(3-Amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide15

[0204] 0.2 g (0.354 mmol) of 412 is dissolved in 10 ml of 4N HCl indioxane and the mixture is stirred at RT for 18 h. After customarywork-up, 0.13 g (76.9%) of 15 is thus obtained as crystals having amelting point of >300° C.; MS(FAB)=466.

1. A semicarbazide of the general formula I,

where: R¹ is —(CH₂)_(n)—NH₂, —CON═C(NH₂)₂, —NHC(═NH)—NH₂ or —C(═NH)—NH₂,which can also be monosubstituted by —OH, —OCOOA, —OCOO(CH₂)_(n)N(A)₂,—OCOO(CH₂)_(m)-Het, —CO—C(A)₂—R⁵, —COOA, —COSA, —COOAr, —COOAr′ or by

R² is H, COOA, R³ is unbranched, branched or cyclic alkyl having 1-20 Catoms, in which one or two CH₂ groups can be replaced by O or S atoms,or is Ar, Ar′, X or Hal, R⁴ is phenyl monosubstituted by S(O)_(k)A,S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CN or OA, R⁵ is —CHal₃, —O(C═O)A or

Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, NHCOA,COOA, CONH₂, CONHA, CONA₂, S(O)_(n)A, S(O)_(n)NH₂, S(O)_(n)NHA,S(O)_(n)NA₂, Ar′ is —(CH₂)_(n)—Ar, Het is a mono- or binuclear,saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/orS atoms, bonded via N or C, which can be unsubstituted or substituted byA, A is H, unbranched, branched or cyclic alkyl having 1-20 C atoms, Xis —(CH₂)_(n)—Y, Y is COOA,

Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 0 or 1, k is 0, 1or 2, l is 0, 1, 2, 3 or 4, or its pharmaceutically tolerable salts andsolvates.
 2. A semicarbazide as claimed in claim 1 of the formula II

where R¹, R³, A and k have the meaning indicated in claim 1 and W isS(O)_(k)A, S(O)_(k)NHA, CF₃, COOA, CH₂NHA, CN or OA, and I is 0, 1 or
 23. A compound as claimed in claim 1 or 2, namely:4′-[3-(3-amidinophenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(1),4′-[3-(3-(N²-hydroxyamidino)phenyl)-2-propylcarbazoylamino]biphenyl-2-sulfonamide(2),4′-[3-(3-amidinophenyl)-2-methylcarbazoylamino]biphenyl-2-sulfonamide(3),1-(3-amidinophenyl)-2-methyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(4),4′-[3-(3-amidinophenyl)-2-ethylcarbazoylamino]biphenyl-2-sulfonamide(5),1-(3-amidinophenyl)-2-ethyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(6),4′-[3-(3-amidinophenyl)-2-isopropylcarbazoylamino]biphenyl-2-sulfonamide(7),1-(3-amidinophenyl)-2-isopropyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(8),4′-[3-(3-amidinophenyl)-2-butylcarbazoylamino]biphenyl-2-sulfonamide(9),1-(3-amidinophenyl)-2-butyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(10),4′-[3-(3-amidinophenyl)-2-isobutylcarbazoylamino]biphenyl-2-sulfonamide(11),1-(3-amidinophenyl)-2-isobutyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(12),4′-[3-(3-amidinophenyl)-2-pentylcarbazoylamino]biphenyl-2-sulfonamide(13),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-pentylsemicarbazide(14),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-ylamino)-2-propylsemicarbazide(15),4′-[3-(3-amidinophenyl)-2-(2-butyl)carbazoylamino]biphenyl-2-sulfonamide(16),1-(3-amidinophenyl)-2-(2-butyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(17),4′-[3-(3-amidinophenyl)-2-(cyclohexylmethyl)carbazoylamino]biphenyl-2-sulfonamide(18),1-(3-amidinophenyl)-2-(cyclohexylmethyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(19),4′-[3-(3-amidinophenyl)-2-benzylcarbazoylamino]biphenyl-2-sulfonamide(20),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(21),1-(3-N-2-hydroxyamidinophenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(22),4′-[3-(3-amidinophenyl)-2-phenylcarbazoylamino]biphenyl-2-sulfonamide(23),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylsemicarbazide(24), methylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(25), 2,2,2-trichloroethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(26), S-ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]thiocarbamate(27), 4-methoxybenzylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(28), ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(29), propylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(30), butylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(31), isopropylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(32), isobutylN-[3-[2-benzyl4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(33), allylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(34), phenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]-phenyl(iminomethyl)]carbamate(35), 2-fluorophenylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(36),2-benzyl-1-[3-(N′-(methylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(37),2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)-1-[3-(N′-(phenylcarboxy)amidino)phenyl]semicarbazide(38),2-benzyl-1-[3-(N′-(isobutylcarboxy)amidino)phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(39),2-benzyl-1-[3-[N′-(2-methylcarboxy-2-propoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(40),2-benzyl-1-[3-[N′-(1-(methylcarboxy)ethoxycarbonyl)amidino]phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(41), 1-methyl-4-piperidinylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(42), 2-(4-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(43), 5-methyl-2-oxo-1,3-dioxol-4-ylmethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(44), 2-(3-pyridyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(45), 2-(N,N-diethylamino)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(46), 2-(N-morpholinyl)ethylN-[3-[2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazido]phenyl(iminomethyl)]carbamate(47), 1-(3-amidinophenyl)-2-(2-fluorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(48),1-(3-amidinophenyl)-2-(2-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(49),1-(3-amidinophenyl)-2-(2-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(50),1-(3-amidinophenyl)-2-(3-chlorobenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(51),4-[1-(3-amidinophenylamino)-3-(2′-methylsulfonylbiphenyl-4-yl)ureidomethyl]-benzoicacid (52),1-(3-amidinophenyl)-2-(3-methylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(53),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(54),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(55),1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethoxybenzyl)semicarbazide(56),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)semicarbazide(57),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluorbiphenyl-4-yl)-semicarbazide(58),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluorbiphenyl-4-yl)-semicarbazide(59),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(60),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3-fluor-biphenyl-4-yl)-semicarbazide(61),1-(3-amidinophenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)semicarbazide(62),1-(3-amidinophenyl)-2-(2-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(63),1-(3-amidinophenyl)-2-(3-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(64),1-(3-amidinophenyl)-2-(4-trifluormethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluor-biphenyl-4-yl)-semicarbazide(65), ethyl2-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-acetate(66), ethyl3-[1-(3-amidinophenylamino)-3-(2′-sulfamoylbiphenyl-4-yl)ureido]-propionate(67),4′-[3-(3-amidinophenyl)-2-[2-(1-methyltetrazol-5-yl)ethyl]carbazoylamino]-biphenyl-2-sulfonamide(68),4′-[3-(3-amidinophenyl)-2-(2-methoxyethyl)carbazoylamino]biphenyl-2-sulfonamide(69),4′-[3-(3-amidinophenyl)-2-(methoxymethyl)carbazoylamino]biphenyl-2-sulfonamide(70),4′-[3-(3-amidinophenyl)-2-(4-methoxybutyl)carbazoylamino]biphenyl-2-sulfonamide(71),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(72),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(73),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(74),1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(75),1-(3-aminomethylphenyl)-2-benzyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)semicarbazide(76),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(2-trifluoromethylbenzyl)semicarbazide(77),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(3-trifluoromethylbenzyl)semicarbazide(78),1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-2-(4-trifluoromethylbenzyl)semicarbazide(79).1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(80),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl4-yl)-semicarbazide(81),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)semicarbazide(82),1-(3-aminomethylphenyl)-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(83),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonylbiphenyl-4-yl)semicarbazide(84),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluoro-biphenyl-4-yl)-semicarbazide(85),1-(3-aminomethylphenyl)-2-benzyl-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(86),1-(3-aminomethylphenyl)-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfony-3,5-difluoro-biphenyl-4-yl)-semicarbazide(87),1-(3-aminomethylphenyl)-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl4-yl)-semicarbazide(88),2-Benzyl-1-[3-(N¹-methoxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(89),2-Benzyl-1-[3-(N1-ethoxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(90),2-Benzyl-1-[3-(N1-vinyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(91),2-Benzyl-1-[3-(N-1-benzyloxy)-amidino)-phenyl]-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(92),2-Benzyl-1-[3-(N1-isopropoxy)-amidino)-phenyl]4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(93),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(94),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(95), 1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(96),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl4-yl)-semicarbazide(97),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(98),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-semicarbazide(99),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3-fluorobiphenyl-4-yl)-semicarbazide(100),1-[3-(N-Hydroxyamidino)-phenyl]-2-benzyl-4-(2′-methylsulfonyl-3,5-difluorobiphenyl-4-yl)-semicarbazide(101),1-[3-(N-Hydroxyamidino)-phenyl]-2-(2-trifluoromethylbenzyl)-4-(2′-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(102),1-[3-(N-Hydroxyamidino)-phenyl]-2-(3-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(103),1-[3-(N-Hydroxyamidino)-phenyl]-2-(4-trifluoromethylbenzyl)-4-(2-methylsulfonyl-3,5-difluoro-biphenyl-4-yl)-semicarbazide(104).
 4. A compound of the formula III:

where P and P′ can be identical or different and are a customaryprotective group for nitrogen and R¹ has the meaning indicated inclaim
 1. 5. A compound of the formula IV

where R¹, R³, P and P′ have the meaning indicated in claims 1 and
 3. 6.A compound of the formula V

where R¹, R³ and P have the meaning indicated in claims 1 and
 3. 7. Acompound of the formula VI

where R¹, R³, R⁴ and P have the meaning indicated in claims 1 and 3 andI is 0, 1, 2, 3 or
 4. 8. A compound of the formula VII

where R¹, R³ and P have the meaning indicated in claims 1 and
 3. 9. Aprocess for the preparation of compounds of the formula I, at least oneof the following reaction steps being carried out: a) reaction ofcompounds of the formula III to give compounds of the formula IV, b)reaction of compounds of the formula IV to give compounds of the formulaV, c) reaction of compounds of the formula V to give compounds of theformula VI, d) reaction of compounds of the formula VI to give compoundsof the formula VII.
 10. A compound of the formula I and/or itsphysiologically acceptable salts or solvates as medicaments.
 11. The useof compounds of the formula I and/or their physiologically acceptablesalts or solvates for the production of a medicament for the control ofthromboses, myocardial infarct, arteriosclerosis, inflammation,apoplexy, angina pectoris, restenosis after angioplasty, intermittentclaudication tumors, tumor diseases and/or tumor metastases.
 12. Apharmaceutical preparation comprising at least one compound of theformula I and/or one of its physiologically acceptable salts orsolvates.